Use of gaba-b receptor positive modulators in gastro-intestinal disorders

ABSTRACT

The invention relates to the use of a compound acting as positive allosteric modulator of GABA B  receptors in the treatment of GERD, regurgitation, IBS, dyspepsia, postoperative complaints and conditions associated with visceral discomfort/pain.

The present invention relates to new pharmaceutical uses of compoundsacting as positive allosteric modulators at γ-aminobutyric acid, type B(GABA_(B)) receptors. They are generically referred to hereinafter asGABA_(B) receptor modulators.

More particularly the invention relates to the use of GABA_(B) receptormodulators in certain gastrointestinal disorders includinggastro-esophageal reflux disease and conditions associated with visceraldiscomfort and pain.

GABA_(B) receptor modulators such as2,6-Di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol and itsaldehyde analog are known for example from Urwyler S. et al., MolecularPharmacology, 2001, 60, 963-971.

Gastro-Esophageal Reflux Disease (GERD) is the most common ailment inthe upper gastrointestinal tract; its cardinal feature and symptom iscommonly known as “heartburn”. A major factor responsible of GERD is anincompetence of the Lower Esophageal Sphincter that opens transientlyand allows passage of acidic material from the stomach into theesophagus. This motor event denominated Transient Lower EsophagealSphincter Relaxation (TLESR) occurs more often in patients sufferingfrom GERD than in healthy subjects and in infants with regurgitation.Current standard therapies in GERD aim at suppressing gastric acidsecretion or enhancing gastrointestinal motility to limit the exposureof the esophagus to acidic gastric contents. Frequent exposure of theesophageal mucosa to acid can trigger pain (often perceived asheartburn) and lead to erosions in the esophagus. Todate, there is notreatment available which actually reduces the occurrence of TLESRs and,thereby, the symptoms of pain associated with GERD or regurgitation ininfants.

Visceral pain and discomfort is not only a symptom of GERD. Patientssuffering from Irritable Bowel Syndrome (IBS), dyspepsia, diseases ofthe biliary tract, pancreas, urinary bladder and postoperativeconditions report pain and discomfort. Visceral hypersensitivity hasbeen discovered as a key phenomenon in many patients suffering fromdiseases like IBS, dyspepsia, GERD and other conditions listed above.Todate, there is no treatment available which specifically treatsvisceral hypersensitivity and, thereby, reduces symptoms of pain anddiscomfort in patients suffering from GERD, IBS, dyspepsia, diseases ofthe biliary tract, pancreas, urinary bladder and postoperativeconditions.

It has recently been reported e.g. in WO 98/11885 that substances actingas agonists at GABA_(B) receptors can reduce TLESRs.

GABA_(B) agonists such as Baclofen play a key role in nervouscircuitries mediating TLESR. For example, GABA_(B) receptors are presentin the nodose ganglion [S. Smid et al., Am. J. Physiol. (2001) 281:G1494-G1501], and the Dorsal Vagal Complex (DVC) [P. Brooks et al., J.Physiol. (1992) 457: 115-129; C. Mc Dermott et al., Gastroenterol.(2001) 120: 1749-1762]. Additionally, Baclofen has been shown to reducethe sensitivity of vagal afferent and efferent fibers [S. Smid et al.,Am. J. Physiol. (2001) 281: G1494-G1501; D. Blackshaw, Br. J. Pharmacol.(2000) 130: 279-288].

Administration of Baclofen reduces the frequency of TLESR in ferrets,[L. A. Blackshaw et al., Am. J. Physiol. (1999) 277: G867-874, dogs [A.Lehmann et al., Gastroenterol. (1999) 117: 1147-1154], in GERD patients[O. Zhang et al., Gut (2002) 50: 19-24] and healthy subjects [I. Lidumset al., Gastroenterol., (2000) 118: 7-13]. Furthermore, long-termrecording of esophageal pH in GERD patients showed a significantreduction in esophageal acid exposure attributable to the reduction ofTLESR by Baclofen [L. Cange, Alim. Pharmacol. & Ther. (2002) 16:869-873].

In accordance with the present invention it has now surprisingly beenfound that substances acting as positive allosteric modulators atGABA_(B) receptors, but lacking classical GABA_(B) receptor agonistactivity, show activity in animal models indicative for use in thetreatment of the pathology of GERD, regurgitation, IBS, dyspepsia, andconditions associated with visceral pain and discomfort, as indicated inexperiments including the following:

In the gastric distension-induced TLESR and crural diaphragm inhibitionmodel in lightly sedated cats according to a modification of Liu J. etal., Am. J. Physiology (2002) 283:G1276-G1281, the receptors modulatorsat doses of 0.1-10 mg/kg (oral or parenteral administration) reduce thefrequency of TLESR and block the inhibition of the crural diaphragmoccurring concomitantly to the TLESR.

In the gastric distension-induced TLESR model in conscious dogs equippedwith a chronic esophagostomy according to a modification of Lehmann A.et al., Gastroenterology (1999) 117:1147-1154, the receptors modulatorsat doses of 0.1-10 mg/kg (oral or parenteral administration) reduce thefrequency of TLESR and reduce the esophageal acid exposure.

In the noxious colorectal distension model in the rat according to amodification of Morteau, O. et al., Dig. Dis. Sci. (1994) 39: 1239-1248[for basics concerning the method, see Ness, T. J. and Gebhart, G. F.,Brain Res. (1988) 450: 153-169; Gebhart, G. F. and Sengupta, J. N., inGaginella, T. A., ed., Methods in gastrointestinal pharmacology, BocaRaton: CRC press (1996), 359-373], the receptor modulators at doses of0.1-10 mg/kg (oral or parenteral administration) reduce responses tocolorectal distension, such as pseudoaffective reflexes or abdominalstriated muscle contractions, indicative of a visceral antinociceptiveactivity.

In the colorectal distension model of hyperalgesia in murine accordingto a modification of Traub, R. T. et al., Neurosci. (1996) 74: 873-884,the receptor modulators at doses of 0.1-10 mg/kg (oral or parenteraladministration) inhibit the expression of immediate early genesfollowing noxious stimulation of afferent fibers, again, indicative of avisceral antinociceptive intervention.

These findings with receptor modulators which lack classical GABA_(B)receptor agonist activity are indicative of therapeutic potential in thetreatment of GERD, regurgitation, IBS, dyspepsia and of conditionsassociated with visceral discomfort/pain.

Moreover, it has been found that positive allosteric modulators at dosesof 0.1-10 mg/kg (parenteral administration) show activity in thepost-operative ileus model according to Huge, A. et al., J. Surg. Res(1998) 74: 112-118, as evidenced by a faster restauration ofgastrointestinal motility as compared to vehicle/placebo treatment.

Hence, it follows that positive allosteric modulators of the GABA_(B)receptor are useful in the treatment of post-operative complaints suchas visceral pain/discomfort and ileus.

For the above-mentioned indications the appropriate dosage will ofcourse vary depending upon, for example, the compound employed, thehost, the mode of administration and the nature and severity of thecondition being treated. However, in general, satisfactory results inanimals are indicated to be obtained at a daily dosage of from about 0.1to about 10 mg/kg body weight. In larger mammals, for example humans, anindicated daily dosage is in the range from about 1 to about 200 mg of areceptor modulator conveniently administered, for example, in divideddoses up to four times a day.

The present invention accordingly provides the use of a receptormodulator in the treatment of the above-mentioned conditions.

For use according to the invention, the GABA_(B) receptor modulator maybe administered as single active agent or in combination with otheractive agents, in any usual manner, e.g. orally, for example in the formof tablets or capsules, or parenterally, for example in the form ofinjection solutions or suspensions.

Moreover, the present invention provides a pharmaceutical compositioncomprising a GABA_(B) receptor modulator in association with at leastone pharmaceutical carrier or diluent for use in the treatment of any ofthe above-indicated diseases. Such compositions may be manufactured inconventional manner. Unit dosage forms may contain, for example, fromabout 0.25 to about 50 mg of the receptor modulator.

The present invention also provides the use of a GABA_(B) receptormodulator for the manufacture of a pharmaceutical composition for thetreatment of any of the above-indicated diseases.

The invention furthermore provides a method for the treatment of any ofthe above-indicated diseases, in a subject in need of such treatment,which comprises administering to said subject a therapeuticallyeffective amount of a GABA_(B) receptor modulator.

1. The use of a compound acting as positive allosteric modulator ofGABA_(B) receptors (a GABA_(B) receptor modulator) in the treatment ofGERD, regurgitation, IBS, dyspepsia, postoperative complaints andconditions associated with visceral discomfort/pain.
 2. The use of aGABA_(B) receptor modulator for the manufacture of a pharmaceuticalcomposition for the treatment of GERD, regurgitation, IBS, dyspepsia,postoperative complaints and conditions associated with visceraldiscomfort/pain.
 3. A pharmaceutical composition comprising a GABA_(B)receptor modulator in association with at least one pharmaceuticalcarrier or diluent, for use in the treatment of GERD, regurgitation,IBS, dyspepsia, postoperative complaints and conditions associated withvisceral discomfort/pain.
 4. A method for treating GERD, regurgitation,IBS, dyspepsia, postoperative complaints and conditions associated withvisceral discomfort/pain in a subject in need of such treatment, whichcomprises administering to said subject a therapeutically effectiveamount of a GABA_(B) receptor modulator.